Cancer Stem Cells: A Minor Cancer Subpopulation that Redefines Global Cancer Features

Heiko Enderling, Lynn Hlatky, Philip Hahnfeldt

In recent years cancer stem cells (CSCs) have been hypothesized to comprise only a minor subpopulation in solid tumors that drives tumor initiation, progression, and metastasis; the so-called "cancer stem cell hypothesis." While a seemingly trivial statement about numbers, much is put at stake. If true, the conclusions of many studies of cancer cell populations could be challenged, as the bulk assay methods upon which they depend have, by, and large, taken for granted the notion that a "typical" cell of the population possesses the attributes of a cell capable of perpetuating the cancer, i.e., a CSC. In support of the CSC hypothesis, populations enriched for so-called "tumor-initiating" cells have demonstrated a corresponding increase in tumorigenicity as measured by dilution assay, although estimates have varied widely as to what the fractional contribution of tumor-initiating cells is in any given population. Some have taken this variability to suggest the CSC fraction may be nearly 100% after all, countering the CSC hypothesis, and that there are simply assay-dependent error rates in our ability to "reconfirm" CSC status at the cell level. To explore this controversy more quantitatively, we developed a simple cellular automaton model of CSC-driven tumor growth dynamics. Assuming CSC and non-stem cancer cells (CC) subpopulations coexist to some degree, we evaluated the impact of an environmentally dependent CSC symmetric division probability and a CC proliferation capacity on tumor progression and morphology. Our model predicts, as expected, that the frequency of CSC divisions that are symmetric highly influences the frequency of CSCs in the population, but goes on to predict the two frequencies can be widely divergent, and that spatial constraints will tend to increase the CSC fraction over time. Further, tumor progression times show a marked dependence on both the frequency of CSC divisions that are symmetric and on the proliferation capacities of CC. Together, these findings can explain, within the CSC hypothesis, the widely varying measures of stem cell fractions observed. In particular, although the CSC fraction is influenced by the (environmentally modifiable) CSC symmetric division probability, with the former converging to unity as the latter nears 100%, the CSC fraction becomes quite small even for symmetric division probabilities modestly lower than 100%. In the latter case, the tumor exhibits a clustered morphology and the CSC fraction steadily increases with time; more so on both counts when the death rate of CCs is higher. Such variations in CSC fraction and morphology are not only consistent with the CSC hypothesis, but lend support to it as one expected byproduct of the dynamical interactions that are predicted to take place among a relatively small CSC population, its CC counterpart, and the host compartment over time.